Pyrazinamide (PZA) is an incredibly important sterilizing agent in the treatment of tuberculosis and is considered responsible for reducing the duration of treatment from the previous 9-12 months, to the current short-course of 6 months produced by the standard regimen (HRZE).Beyond its contribution in the current first-line regimen, the TB Alliance, through its ongoing novel regimen development program is finding that PZA is critical to any treatment shortening regimen, including those that contain newer agents currently in clinical development. PZA has the ability to synergize with other drugs and this synergy drives the treatment-shortening potential of experimental regimens, such as PaMZ (PA-824 + moxifloxacin + pyrazinamide) currently under clinical development. However, resistance to PZA is on the rise, creating potential problems for PZA-containing regimens in development. Yet, there may be ways to circumvent this resistance. Investigating whether this is possible is the focus of a 1-year, $250,000 grant from the US NIH ACTG.
The mechanism of PZA resistance is mostly due to mutations in an intrinsic mycobacterial pyrazinamidase (PncA), an enzyme that hydrolyses pyrazinamide to its active form, pyrazinoic acid (POA). If we can deliver POA without depending on pyrazinamidase, then theoretically we can overcome PZA resistance and we can extend the life of this amazing drug.
The method proposed in this research utilizes another intrinsic mycobacterial enzyme, a beta-lactamase, to hydrolyze synthetic beta-lactam-POA conjugates, and deliver POA into the pathogen without utilizing PncA. We will take advantage of this powerful enzyme to deliver POA. This kind of approach has been used in cancer chemotherapy to deliver drugs specifically to tumor cells.
Furthermore, since this delivery method would take a more direct path to the target, it has the potential to reduce toxicity to the patient. If successful, this technique could be applied to the delivery of additional TB drugs to further reduce toxicity and increase efficacy. This exciting program is the first step in finding out whether such innovations are possible.
The project is collaboration of three parties, TB Alliance, Prof. Kyu Rhee of Weil Cornell Medical College and Prof. Kelly Chiballe of the University of Cape Town. Dr. Chiballe recently made headlines for his research into single-dose cures for some strains of malaria. TB Alliance has generated preliminary results supporting the hypotheses to be tested in this work with the help of Prof. John Blanchard of AECOM and Prof. Taegwon Oh of Yonsei University.